 |
Discover ~ Translate ~ Cure |
|
Discover ~ Translate ~ Cure |
| Title |
| Phase II Study of a HER-2/neu (HER2) Intracellular Domain (ICD) Peptide-Based Vaccine Administered to Stage IIIB and IV HER2 Positive Breast Cancer Patients Receiving Trastuzumab Monotherapy |
| Study Design |
| This will be a phase II, single arm clinical trial in patients with HER2 overexpressing Stage IIIB and IV breast cancer who have previously been treated with trastuzumab alone or in combination with chemotherapy and are NED or have stable bone only disease and are currently on maintenance trastuzumab. Patients will receive a monthly vaccination for 6 months with a HER2 ICD peptide-based vaccine. |
| Study Contact |
| Nicole Bates | 206.543.6620 | E-Mail |
| Rationale |
| The HER2 ICD vaccine immunizes patients with CD4+ T helper (Th) epitopes derived from the HER2 protein. Vaccinating to elicit a T helper response has resulted in the development of immunologic memory as well as the augmentation of antibody and cytotoxic T lymphocyte (CTL) immunity specific for HER2 in Phase I studies. Either antibody or cellular immunity has the potential for an anti-tumor effect. Among 11 subjects who completed 6 vaccinations, all developed significant T cell responses to the vaccinated peptides and 9 to a protein domain of HER2. Furthermore, 7 developed T cell immunity to HER2 epitopes that were not part of the vaccination mix i.e. intramolecular epitope spreading (1). We now have preliminary 5 year follow-up data on these patients demonstrating persistence of the immune response after active immunization has ended, including precursor frequencies of IFN-gamma secreting T cells in the range of 1:20,000 and 1:12,000 for HER2 peptide and protein, respectively. Data from the phase I trial of the ICD vaccine demonstrated that immunizations were safe. The CTL has been considered the primary immune effector involved in mediating an anti-tumor response. Recent studies have demonstrated that “sensitization” of HER2 overexpressing tumor cells with trastuzumab, in vitro, will enhance the function of CTL specific for HER2. Theoretically, the mechanism of trastuzumab enhancement of a HER2 specific CTL response might be the internalization of the HER2 receptor, degradation of the HER2 protein, and increased presentation of the HER2 protein via MHC class I. Thus, co-administration of trastuzumab and HER2 ICD peptide based vaccine may result in the potentiation of a HER2 specific CTL response in breast cancer patients. A benefit of the HER2 ICD peptide based vaccine is that the epitopes included are not restricted to any particular HLA type. It is probable that immunizing with these 15 mer epitopes derived from the ICD will result in presentation of class I epitopes for the generation of a HER2 specific CTL response (2). One of the drawbacks to the assessment of CD8+ T cell responses is the need to develop targets that are HLA matched for each patient to evaluate immunity. Recently, it has been shown that peptide pools of 15 amino acid peptides with 11 amino acid overlaps can be used to accurately assess CD4+ or CD8+ T cell responses simultaneously. That is, overlapping peptide pools spanning the entire molecule are a surrogate target for both recombinant protein as well as HLA matched antigen expressing tumor cells. We have constructed overlapping peptide pools for the HER2 molecule and will determine both the CD4+ and CD8+ T cell response to the HER2 ICD protein. This proposal outlines a Phase II clinical trial designed to estimate survival in Stage IIIB and IV HER2 overexpressing breast cancer patients receiving trastuzumab monotherapy and a HER2 ICD peptide based vaccine. Stage IIIB and IV HER2 positive breast cancer patients will have been treated with trastuzumab alone or in combination with chemotherapy to NED or stable bone only disease and then while on maintenance trastuzumab, will receive vaccination. In addition to survival we will assess the safety of combined immunotherapy, the immunogenicity of the approach, and whether the development of HER2 specific immunity correlates with clinical response. |
| Study Population / Indication |
| Patients with HER2 overexpressing Stage IIIB or IV breast cancer who have previously been treated with trastuzumab alone or in combination with chemotherapy, have no evidence of disease (NED) or stable bone only disease, and are currently on maintenance trastuzumab. |
| Number of Patients: This study will accrue a maximum of 52 patients. This will provide statistically adequate numbers of subjects for gathering (1) overall survival data to compare to historical controls, (2) safety data, (3) immunologic response data to assess the incidence and magnitude of the HER2-specific immune response generated, and (4) data to evaluate the association between OS and immune response. |
| Start Date: June 2006 |
| Study Location: University of Washington Medical Center | 1959 NE Pacific Street | Seattle, WA 98195 |
| Current Enrollment: 19% |
| Objectives |
Primary:
|
| Outcome Measures |
Primary endpoints:
|
| Related Publications |
|
Generation of T cell immunity to the HER-2/neu protein after active immunization with HER-2/neu peptide-based vaccines Disis ML, Gooley TA, Rinn K, Davis D, Piepkorn M, Cheever MA, Knutson KL, Schiffman K J Clinical Oncology 20(11): 2624-32, 2002 |
| Clinical Description |
| ClinicalTrials.gov Identifier: NCT00343109 |
Page last updated 4/27/09 |